The present invention relates to novel bis-sulfonamides of the general formula I and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula I and especially their use as endothelin antagonists.
Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid peptides produced and active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332:411). Endothelins are potent vasoconstrictors and important mediators of cardiac, renal, endocrine and immune functions (McMillen M A et al.: J Am Coll Surg (1995) 180:621). They participate in bronchoconstriction and regulate neurotransmitter release, activation of inflammatory cells, fibrosis, cell proliferation and cell differentiation (Rubanyi G M et al.: Pharmacol Rev (1994) 46:328).
Two endothelin receptors have been cloned and characterized in mammals (ETA, ETB) (Arai H et al.: Nature (1990) 348:730; Sakurai T et al.: Nature (1990) 348:732). The ETA receptor is characterized by higher affinity for ET-1 and ET-2 than for ET-3. It is predominant in vascular smooth muscle cells and mediates vasoconstricting and proliferative responses (Ohlstein E H et al.: Drug Dev Res (1993) 29:108). In contrast, the ETB receptor has equivalent affinity for the 3 endothelin isopeptides and binds the linear form of endothelin, tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991) 178:248). This receptor is located in the vascular endothelium and smooth muscles, and is also particularly abundant in lung and brain. The ETB receptor from endothelial cells mediates transient vasodilator responses to ET-1 and ET-3 through the release of nitric oxide and/or prostacyclin whereas the ETB receptor from smooth muscle cells exerts vasoconstricting actions (Sumner M J et al.: Brit J Pharmacol (1992) 107:858). ETA and ETB receptors are highly similar in structure and belong to the superfamily of G-protein coupled receptors.
A pathophysiological role has been suggested for ET-1 in view of its increased plasma and tissue levels in several disease states such as hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive heart failure, renal failure, migraine and asthma. As a consequence, endothelin receptor antagonists have been studied extensively as potential therapeutic agents. Endothelin receptor antagonists have demonstrated preclinical and/or clinical efficacy in various diseases such as cerebral vasospasm following subarachnoid hemorrhage, heart failure, pulmonary and systemic hypertension, neurogenic inflammation, renal failure and myocardial infarction.
Today, no endothelin receptor antagonist is marketed yet, several are in clinical trials. However, these molecules possess a number of weaknesses such as complex synthesis, low solubility, high molecular weight, poor pharmacokinetics, or safety problems (e.g. liver enzyme increases). Furthermore, the contribution of differential ETA/ETB receptor blockade to the clinical outcome is not known. Thus, tailoring of the physicochemical and pharmacokinetic properties as well as the selectivity profile of each antagonist for a given clinical indication is mandatory. We have discovered a new class of bis-sulfonamide compounds of the structure below and found that they allow the specific tailoring described above.
The inhibitory activity of the compounds of formula I on endothelin receptors can be demonstrated using the test procedures described hereinafter:
For the Evaluation of the Potency and Efficacy of the Compounds of the General Formula I the Following Tests Were Used
1) Inhibition of Endothelin Binding to Membranes from CHO Cells Carrying Human ET Receptors:
For competition binding studies, membranes of CHO cells expressing human recombinant ETA or ETB receptors were used. Microsomal membranes from recombinant CHO cells were prepared and the binding assay made as previously described (Breu V., et al, FEBS Lett 1993; 334:210).
The assay was performed in 200 uL 50 mM Tris/HCl buffer, pH 7.4, including 25 mM MnCl2, 1 mM EDTA and 0.5% (w/v) BSA in polypropylene microtiter plates. Membranes containing 0.5 ug protein were incubated for 2 h at 20xc2x0 C. with 8 pM [125I]ET-1 (4000 cpm) and increasing concentrations of unlabelled antagonists. Maximum and minimum binding were estimated in samples without and with 100 nM ET-1, respectively. After two h, the membranes were filtered on, filterplates containing GF/C filters (Unifilterplates from Canberra Packard S. A. Zxc3xcrich, Switzerland). To each well, 50 uL of scintillation cocktail was added (MicroScint 20, Canberra Packard S. A. Zxc3xcrich, Switzerland) and the filter plates counted in a microplate counter (TopCount, Canberra Packard S. A. Zxc3xcrich, Switzerland).
All the test compounds were dissolved, diluted and added in DMSO. The assay was run in the presence of 2.5% DMSO which was found not to interfere significantly with the binding. IC50 was calculated as the concentration of antagonist inhibiting 50% of the specific binding of ET-1. For reference compounds, the following IC50 values were found: ETA cells: 0.075 nM (n=8) for ET-1 and 118 nM (n=8) for ET-3; ETB cells: 0.067 nM (n=8) for ET-1 and 0.092 nM (n=3) for ET-3.
The IC50 values obtained with compounds of formula I are given in Table 1
2) Inhibition of Endothelin-induced Contractions on Isolated Rat Aortic Rings (ETA Receptors) and Rat Tracheal Rings (ETB Receptors)
The functional inhibitory potency of the endothelin antagonists was assessed by their inhibition of the contraction induced by endothelin-1 on rat aortic rings (ETA receptors) and of the contraction induced by sarafotoxin S6c on rat tracheal rings (ETB receptors). Adult Wistar rats were anesthetized and exsanguinated. The thoracic aorta or trachea were excised, dissected and cut in 3-5 mm rings. The endothelium/epithelium was removed by gentle rubbing of the intimal surface. Each ring was suspended in a 10 ml isolated organ bath filled with Krebs-Henseleit solution (in mM; NaCl 115, KCl 4.7, MgSO4 1.2, KH2PO4 1.5, NaHCO3 25, CaCl2 2.5, glucose 10) kept at 37xc2x0 and gassed with 95% O2 and 5% CO2. The rings were connected to force transducers and isometric tension was recorded (EMKA Technologies SA, Paris, France). The rings were stretched to a resting tension of 3 g (aorta) or 2 g (trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6c (trachea) were added after a 10 min incubation with the test compound or its vehicle. The functional inhibitory potency of the test compound was assessed by calculating the concentration ratio, i.e. the shift to the right of the EC50 induced by different concentrations of test compound. EC50 is the concentration of endothelin needed to get a half-maximal contraction, pA2 is the negative logarithm of the antagonist concentration which induces a two-fold shift in the EC50 value.
The pA2 values obtained with compounds of formula I are given in Table 2.
Because of their ability to inhibit the endothelin binding, the described compounds can be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud""s syndrome, portal hypertension and pulmonary hypertension. They can also be used for atherosclerosis, prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to endothelin.
The compounds can be administered orally, rectally, parenterally, e.g. by intravenous, intramuscular, subcutaneous, intrathecal or transdermal administration or sublingually or as ophthalmic preparation or administered as aerosol. Examples of applications are capsules, tablets, orally administered suspensions or solutions, suppositories, injections, eye-drops, ointments or aerosols/nebulizers.
Preferred applications are intravenous, intramuscular, or oral administrations as well as eye drops. The dosage used depends upon the type of the specific active ingredient, the age and the requirements of the patient and the kind of application. Generally, dosages of 0.1-050 mg/kg body weight per day are considered. The preparations with compounds can contain inert or as well pharmacodynamically active excipients. Tablets or granules, for example, could contain a number of binding agents, filling excipients, carrier substances or diluents.
The present invention relates to bis-sulfonamides of the general formula I, 
wherein
R1 represents aryl; aryl-lower alkyl; aryl-lower alkenyl; heteroaryl; heteroaryl-lower alkyl;
R2 represents lower alkyl; trifluoromethyl; lower alkoxy-lower alkyl; lower alkenyl; lower alkynyl; aryl; aryl-lower alkyl; aryl-lower alkenyl; heterocyclyl; heterocyclyl-lower alkyl; heteroaryl; heteroaryl-lower alkyl; cycloalkyl; cycloalkyl-lower alkyl;
R3 represents phenyl; mono-, di- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkynyl, lower alkyloxy, amino, lower alkylamino, amino-lower alkyl, trifluoromethyl, trifluoromethoxy, halogen, lower alkylthio, hydroxy, hydroxy-lower alkyl, cyano, carboxyl, lower alkanoyl, formyl; benzofuranyl; aryl; heteroaryl;
R4 represents hydrogen; halogen; trifluoromethyl; lower alkyl; lower alkyl-amino; lower alkyloxy; lower alkyl-sulfono; lower alkyl-sulfinyl; lower alkylthio; lower alkylthio-lower alkyl; hydroxy-lower alkyl; lower alkyl-oxy-lower alkyl; hydroxy-lower alkyl-oxy-lower alkyl; hydroxy-lower alkyl-amino; lower alkyl-amino-lower alkyl, amino; di-lower alkyl-amino; [N-(hydroxy-lower alkyl)-N-(lower alkyl)]-amino; aryl; aryl-amino; aryl-lower alkyl-amino; aryl-thio; aryl-lower alkyl-thio; aryloxy; aryl-lower alkyl-oxy; aryl-lower alkyl; aryl-sulfinyl; heteroaryl; heteroaryl-oxy; heteroaryl-lower alkyl-oxy; heteroaryl-amino; heteroaryl-lower alkyl-amino; heteroaryl-thio; heteroaryl-lower alkyl-thio; heteroaryl-lower alkyl; heteroaryl-sulfinyl; heterocyclyl; heterocyclyl-lower alkyl-oxy; heterocyclyl-oxy; heterocyclyl-amino; heterocyclyl-lower alkyl-amino; heterocyclyl-thio; heterocyclyl-lower alkyl-thio; heterocyclyl-lower alkyl; heterocyclyl-sulfinyl; cycloalkyl; cycloalkyl-oxy; cycloalkyl-lower alkyl-oxy; cycloalkyl-amino; cycloalkyl-lower alkyl-amino; cycloalkyl-thio; cycloalkyl-lower alkyl-thio; cycloalkyl-lower alkyl; cycloalkyl-sulfinyl;
R6 represents hydrogen; lower alkyl; cycloalkyl; heterocyclyl; heteroaryl; aryl; cycloalkyl-lower alkyl; heterocyclyl-lower alkyl; heteroaryl-lower alkyl; aryl-lower alkyl; lower alkoxy-lower alkyl; lower alkyl-thio-lower alkyl; lower alkyl-amino-lower alkyl; lower alkenyl; lower alkynyl;
n represents the numbers 2, 3, 4 and 5;
X represents oxygen; sulfur; NH; CH2 or a bond;
and pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and the meso-forms and pharmaceutically acceptable salts thereof.
In the definitions of the general formula Ixe2x80x94if not otherwise statedxe2x80x94the expression lower means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms. Examples of lower alkyl and lower alkoxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, hexyl, heptyl, methoxy, ethoxy, propoxy, butoxy, iso-butoxy, sec.-butoxy and tert.-butoxy. Lower alkylendioxy-groups are preferably methylen-dioxy, ethylen-dioxy, propylen-dioxy and butylen-dioxy-groups. Examples of lower alkanoyl-groups are acetyl, propanoyl and butanoyl. Lower alkenylen means e.g.vinylen, propenylen and butenylen. Lower alkenyl and lower alkynyl means groups like ethylen, propylen, butylen, 2-methyl-propenyl, and ethinylen, propinylen, butinylen, pentinylen, 2-methyl-pentinylen etc. Lower alkenyloxy means allyloxy, vinyloxy, propenyloxy and the like. The expression cycloalkyl means a saturated cyclic hydrocarbon ring with 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which may be substituted with lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkoxy-lower alkyl and lower alkenylen groups. The expression heterocyclyl means saturated or unsaturated (but not aromatic) four, five-, six- or seven-membered rings containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which rings may be substituted with lower alkyl, amino, nitro, hydroxy, lower alkoxy, e.g. piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, pyrazolidinyl etc. and substituted derivatives of such rings with substituents as outlined above. The expression heteroaryl means six-membered aromatic rings containing one to four nitrogen atoms, benzofused six-membered aromatic rings containing one to three nitrogen atoms, five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, benzo-fused five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, five membered aromatic rings containig an oxygen and nitrogen atom and benzo fused derivatives thereof, five membred aromatic rings containing a sulfur and a nitrogen atom and benzo fused derivatives thereof, five-membered aromatic rings containing two nitrogen atoms and benzo fused derivatives thereof, five membered aromatic rings containing three nitrogen atoms and benzo fused derivatives thereof or the tetrazolyl ring e.g. furanyl, thienyl, pyrrolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, thiazolyl, isothiazolyl, pyridazinyl, oxazolyl, isoxazolyl, etc. whereby such rings may be substituted with lower alkyl, lower alkenyl, amino, amino-lower alkyl, halogen, hydroxy, lower alkoxy, trifluoromethoxy or trifluoromethyl. The expression aryl represents unsubstituted as well as mono-, di- or tri-substituted aromatic rings with 6 to 10-carbon atoms like phenyl or naphthyl rings which may be substituted with aryl, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower alkenyloxy, lower alkynyl-lower alkyl-oxy, lower alkenylen, lower alkylenoxy, lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkyl-lower alkynyl, lower alkyloxy-lower alkyl, lower alkyloxy-lower alkyloxy, trifluoromethyl, trifluoromethoxy, cycloalkyl, hydroxy-cycloalkyl, heterocyclyl, heteroaryl.
Especially preferred compounds are compounds of formula I wherein R3 represents phenyl or mono-substituted phenyl substituted with lower alkyloxy, especially methoxy, X represents oxygen and n represents the numbers 2 or 3.
A second group of especially preferred compounds of formula I are the compounds wherein R3 represents phenyl or monosubstituted phenyl substituted with lower alkyl, especially methyl, or lower alkoxy, especially methoxy, X represents a bond and n represents the numbers 2 or 3.
The expression pharmaceutically acceptable salts encompasses either salts with inorganic acids or organic acids like hydrohalogenic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p-toluolsulfonic acid and the like or in case the compound of formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide etc. The compounds of the general formula I have one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and also in the meso-form. The present invention encompasses all these forms. Mixtures may be separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC, crystallization etc.
Because of their ability to inhibit the endothelin binding, the described compounds of the general formula I and their pharmaceutically acceptable salts may be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud""s syndrome, portal hypertension and pulmonary hypertension. They can also be used for atherosclerosis, prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to endothelin.
These compositions may be administered in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectically in form of suppositories. These compounds may also be administered in intramuscular, parenteral or intraveneous form, e.g. in form of injectable solutions.
These pharmaceutical compositions may contain the compounds of formula I as well as their, pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.
For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used. For the preparation of solutions and sirups e.g. water, polyols, saccharose, glucose etc. are used. Injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes etc. Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats), liquid or half-liquid polyols etc.
The compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, anti oxidants etc.
The compounds of formula I may also be used in combination with one or more other therapeutically useful substances e.g. xcex1- and xcex2-blockers like Phentolamine, Phenoxybenzamine, Atenolol, Propranolol, Timolol, Metoprolol, Carteolol etc.; Vasodilators like Hydralazine, Minoxidil, Diazoxide, Flosequinan etc.; Calcium-antagonists like Diltiazem, Nicardipine, Nimodipine, Verapamil, Nifedipine etc.; ACE-inhibitors like Cilazapril, Captopril, Enalapril, Lisinopril etc.; Potassium activators like Pinacidil etc. Angiotensin II antagonists; Diuretics like Hydrochlorothiazide, Chlorothiazide, Acetolamide, Bumetanide, Furosemide, Metolazone, Chlortalidone etc.; Sympatholitics like Methyldopa, Clonidine, Guanabenz, Reserpine etc.; and other therapeutics which serve to treat high blood pressure or any cardiac disorders.
The dosage may vary within wide limits but should be adapted to the specific situation. In general the dosage given in oral form should daily be between about 3 mg and about 3 g, preferably between about 10 mg and about 1 g, especially preferred between 5 mg and 300 mg, per adult with a body weight of about 70 kg. The dosage should be administered preferably in 1 to 3 doses per day which are of equal weight. As usual children should receive lower doses which are adapted to body weight and age.
Preferred compounds are compounds of formula II 
wherein R1, R2, R4, R6 and n are as defined in formula I above,
and pharmaceutically acceptable salts of compounds of formula II.
Especially preferred compounds among the group of compounds of formula II are those wherein R6 represents hydrogen or lower alkyl.
Also preferred are compounds of formula III 
wherein R1, R2, R4 and R6 are as defined in formula I above,
and pharmaceutically acceptable salts of compounds of formula III.
Especially preferred compounds among the group of compounds of formula III are those wherein R6 represents hydrogen or lower alkyl.
Also preferred are compounds of formula IV 
wherein R2, R4 and R6 are as defined in formula I above and R5 represents hydrogen, methyl or isopropyl,
and pharmaceutically acceptable salts of compounds of formula IV.
Especially preferred compounds among the group of compounds of formula IV are those wherein R6 represents hydrogen or lower alkyl.
Another preferred group of compounds are compounds of formula V 
wherein R5 is as defined in formula IV above, R2 and R6 are as defined in formula I above, U and V represent nitrogen and W represents carbon, or U and V represent carbon and W represents nitrogen,
and pharmaceutically acceptable salts thereof.
Especially preferred compounds among the group of compounds of formula V are those wherein R6 represents hydrogen or lower alkyl.
Another preferred group of compounds are compounds of formula VI 
wherein R1, R2, R3, R4, R6 and n are as defined in formula I above,
and pharmaceutically acceptable salts of compounds of formula VI.
Especially preferred compounds among the group of compounds of formula VI are those wherein R6 represents hydrogen or lower alkyl.
Another preferred group of compounds are compounds of formula VII 
wherein R1, R2, R4, R6 and n are as defined in formula I above,
and pharmaceutically acceptable salts of compounds of formula VII.
Especially preferred compounds among the group of compounds of formula VII are those wherein R6 represents hydrogen or lower alkyl.
Preferred compounds are:
p-tert.-butyl-N-[6-(ethoxy-2-(2-thiophenesulfonamido))-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamide,
5-i.-propyl-N-[6-(ethoxy-2-(2-propanesulfonamido))-5-(o-methoxyphenoxy)2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamide,
5-i.-propyl-N-[6-(ethoxy-2-(4-methylbenzenesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,
5-i.-propyl-N-[6-(ethoxy-2-(4-methylbenzenesulfonamido)5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamide,
5-i.-propyl-N-[6-(ethoxy-2-benzenesulfonamido)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]pyridine-2-sulfonamide,
5-i.-propyl-N-[6-(ethoxy-2-thiophenesulfonamido)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,
5-i.-propyl-N-[6-(ethoxy-2-(1-propanesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,
p-tert.-butyl-N-[6-(ethoxy-2-(1-butanesulfonamido))-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamide,
5-i.-propyl-N-[6-(ethoxy-2-p-toluenesulfonamido)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]pyridine-2-sulfonamide,
5-i.-propyl-N-[6-(ethoxy-2-methanesulfonamido)-5-(o-methoxyphenoxy)-2-methyl4-pyrimidinyl]pyridine-2-sulfonamide,
4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-2-methanesulfonyl-5-(o-methoxyphenoxy-pyrimidin-4-yl]-benzenesulfonamide,
5-i-propyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide,
5-i-propyl-N-[6-(2-(4-methylbenzene)-sulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide,
4-tert.-butyl-N-[6-(2-(2-propane)-sulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide,
5-isopropyl-N-[6-(2-(2-thiophensulfonyl)-amino-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide,
5-i-propyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-pyridine-2-sulfonamide,
5-isopropyl-N-[6-(2-propanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide,
5-methyl-N-[6-(2-(1-propanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide,
5-isopropyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide,
and pharmaceutically acceptable salts thereof.
Particularly preferred compounds are
p-tert.-butyl-N-[6-(ethoxy-2-(2-thiophenesulfonamido))-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene-sulfonamide,
5-i.-propyl-N-[6-(ethoxy-2-(4-methylbenzenesulfonamido))-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,
5-i.-propyl-N-[6-(ethoxy-2-thiophenesulfonamido)-5-(o-methoxyphenoxy)-2-(3,4,5-trimethoxyphenyl)-4-pyrimidinyl]pyridine-2-sulfonamide,
5-isopropyl-N-[6-(2-(4-methylbenzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide,
5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide
5-isopropyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide
4-tert.-butyl-N-[6-(3-(ethanesulfonylamino)-propoxy)5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide
4-tert.-butyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-pyrimidinyl-4-pyrimidinyl]-benzene-sulfonamide
4-tert.-butyl-N-[6-(3-(ethanesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-benzene-sulfonamide
4-tert.-butyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-benzene-sulfonamide
5-i.-propyl-N-[6-(3-(propanesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide
5-i.-propyl-N-[6-(3-(2-thiophenesulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide
5-i.-propyl-N-[6-(3-(p-toluenesulfonylamino)-propoxy)-5(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]-pyridine-2-sulfonamide
and pharmaceutically acceptable salts thereof.
The invention also relates to a process for the manufacture of compounds of the general formula I: 
wherein R1, R2, R4, R6, X and n have the meaning given in formula I above,
which process comprises
a) for obtaining compounds wherein R6 represents hydrogen, reacting a compound of formula VIII 
wherein R1, R3,R4, X and n have the meaning given in formula I above,
with a compound of the formula Clxe2x80x94SO2xe2x80x94R2, wherein R2 has the meaning given in formula I above, or
b) by reacting a compound of formula IX 
wherein R1, R3, R4 and X have the meaning given in formula I above, with a compound of formula X 
wherein R2, R6 and n have the meaning given in formula I above,
and, as the case may be, resolving a compound with one or more optically active carbon atoms into pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, or into the meso-form in a manner known per se.
and, if desired, converting a compound of formula I obtained into a pharmaceutically acceptable salt in a manner known per se.
The above process may be described in more detail as follows:
The compounds of the general formula I of the present invention wherein R6 represents hydrogen, are prepared according to the general sequence of reactions outlined in Scheme 1 below, wherein R1,R2,R3,R4 and n are as defined in formula I above. For simplicity and clarity reasons Scheme I only describes part of the synthetic possibilities which lead to compounds of formula I. The literature references given in brackets [ ] are set forth at the end of this paragraph. The amidines 2 were synthesized applying standard methodology [1] by reaction of the appropriate nitrile 1 either with sodium methylate in methanol followed by addition of ammonium chloride or by reaction with lithium hexamethyldisilazane followed by addidion of hydrochloric acid in i-propanol. The 2-substituted malonic esters 4 were prepared accoring to published procedures [1] by reacting dimethylchloromalonate (3) with the appropriate alcohol 5 in acetone and potassium carbonate as base. The compounds 4 were dissolved in methanol and sodium methylate was added and stirring was continued for about 30 min followed by the addition of an amidine derivative 2. Stirring at ambient temperature was continued for another 8 h. After acidic work up the 4,6-dihydroxypyrimidines 6 could be isolated in yields of 70 to 90% [2]. Compounds 6 or the tautomeric form thereof were transformed into the dichloroderivatives 7 with phosphorous oxychloride at elevated temperatures (60-120xc2x0 C.) in yields of 40 to 75% [3]. In some cases better yields were obtained by addition of PCl5 or benzyl-triethylammoniumchloride. The dichlorides 7 were reacted with an excess of the appropriate sulfonamide potassium salt 9 (prepared according to standard methodology from the sulfochlorides 8) in DMSO at room temperature to give the pyrimidines 10 in yields of 70 to 90% either after recrystallization from ethyl acetate/diethylether or chromatography over silica gel with ethyl acetate/heptane. The pyrimidine derivatives 10 are the central intermediates which can be transformed to the desired final products by two different pathways. Depending on the nature of R1, R3 and R4 the suitable reaction sequence is chosen. The first possibility to transform 10 into the final products 13 is by reaction with the 1-hydroxy-xcfx89-sulfonamido-alkyl-compounds 12 (prepared from the appropriate 1,xcfx89-aminoalcohol 11 and the sulfochlorides 15 at room temperature in THF) in THF/DMSO=15/1 and potassium tert.-butylate as base at elevated temperatures (60 to 120xc2x0 C. in yields of 40 to 80%. The second reaction sequence starts with the introduction of the oxy-alkyl-amino side chain by reaction of 10 with the appropriate 1,xcfx89-aminoalcohol 11 in THF/DMF=1/1 and sodium hydride as base to give compounds 14 in yields of 50 to 70% after recrystallization. The alkylamino functionality of 14 was then reacted by standard methodology [4] with the desired sulfochlorides 15 in methylene chloride and Hxc3xcnig""s base to give the target bis-sulfonamides 13 in yields of 40 to 75% after recrystallization from mixtures of methanol/acetonitrile and/or diethyl ether.
Compounds of general formula I wherein R1, R2, R3, R4, X and n are as defined in general formula I above and wherein R6 is as defined in general formula I above but does not represent hydrogen, can be prepared according to Scheme 2. For simplicity and clarity reasons, Scheme 2 only describes part of the synthetic possibilities which lead to compounds of formula I. Compounds 16, prepared according to the description given in Scheme 1 and [5], [6] are reacted with compounds 18 under the same reaction conditions given for the synthesis of compounds 13 to give compounds 19 (which correspond to compounds of general formula I). Compounds 18 are obtained by reacting the aminoalcohol derivatives 17 with the sulfochlorides 15 under the conditions described in Scheme 1. Compounds 17 are either commercially available or can be prepared by standard procedures (reductive amination, alkylation etc) from aminoalcohols or from the hydroxy protected aminoalcohols containing a primary amino group.
[1] W. Gxc3x6hring, J. Schildknecht, M. Federspiel; Chimia, 1996, 50, 538-543
[2] W. Neidhart, V. Breu, D. Bur, K. Burri, M. Clozel, G. Hirth, M. Mxc3xcller, H. P. Wessel, H. Ramuz; Chimia, 1996, 50, 519-524 and references cited there.
[3] W. Neidhart, V. Breu, K. Burri, M. Clozel, G. Hirth, U. Klinkhammer, T. Giller, H. Ramuz; Bioorg. Med. Chem. Lett., 1997, 7, 2223-2228. R. A. Nugent, S. T. Schlachter, M. J. Murphy, G. J. Cleek, T. J. Poel, D. G. Whishka, D. R. Graber, Y. Yagi, B. J. Keiser, R. A. Olmsted, L. A. Kopta, S. M. Swaney, S. M. Poppe, J. Morris, W. G. Tarpley R. C. Thomas; J. Med. Chem., 1998, 41, 3793-3803.
[4] J. March; Advanced Organic Chemistry, 4th Ed., 1994, p. 499 and references cited there.
[5] EP 0 743 307 A1; EP 0 658 548 B1; EP 0 959 072 A1 (Tanabe Seiyaku)
[6] EP 0 633 259 B1; EP 0 526 708 A1; WO 96/19459 (F. Hofmann-LaRoche) 
According to the procedures described in [5] and for Schemes 1 and 2 compounds of the general formula I can also be prepared as displayed in Scheme 3 below wherein R1, R2, R3, R4, R6, X and n are as defined in general formula I: 
a) i) thiourea, NaOMe, MeOH, rt; ii) Mel, DMSO, rt; iii) POCl3, dimethylaniline, 100-120xc2x0 C.; b) R1xe2x80x94SO2xe2x80x94NHK, DMSO, rt; c) 18, KOtBu, THF, rflx; d) MCPBA, DCM, rt; ii) for the substitution of the sulfono group see [5]; e) HOxe2x80x94(CH2)nxe2x80x94NH2, NaH, THF/DMF, 0xc2x0 C. to rt; f) R2xe2x80x94SO2xe2x80x94Cl, base, DCM, rt; g) MCPBA, DCM, rt; h) for the substitution of the sulfono group see [5].